Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
ROLE OF THE HIV TAT GENE IN TRANSFORMATION OF HUMAN KERATINOCYTES IN CULTURE AND INDUCTION OF TUMORS IN TRANSGENIC MICE (MEETING ABSTRACT)
Workshop on Neoplastic Transformation in Human Cell Systems In Vitro: Mechanisms of Carcinogenesis, April 25-26, 1991, Washington, DC, p. S14, 1991.. Unique Identifier : AIDSLINE ICDB/92678305 Jay G; Vogel J; Kim CM; Rhim JS; Lab. of Virology, Jerome H. Holland Lab., Rockville, MD
Abstract:
Patients (pts) with the acquired immunodeficiency syndrome (AIDS) frequently present with cutaneous disorders, such as Kaposi's sarcoma, psoriasis, squamous cell carcinoma, basal cell carcinoma, and melanoma. Since these individuals are frequently infected not only by the human immunodeficiency virus (HIV) but also by other agents including the human papilloma virus, it is not clear whether the development of any of these skin manifestations is directly attributable to HIV. Given that HIV carries a potent transactivator gene, designated tat, which acts to regulate viral genes, we reasoned that it may also perturb the expression of cellular genes leading ultimately to the development of disease. To explain the psoriatic lesions detected in AIDS pts, we ask whether the HIV tat gene under the control of its own regulatory element (LTR) will transform epidermal keratinocytes in culture. We observed that human keratinocytes transfected with this gene alone showed extensive morphological alterations, grew efficiently in soft agar, and induced tumors in nude mice. This observation would suggest that the psoriatic lesions detected in HIV-infected individuals may be directly caused by the expression of viral genes in the proliferating keratinocytes. As a further analysis, we have introduced the same HIV tat gene under the control of the viral LTR into the germline of mice in order to define HIV pathogenesis in the context of a whole animal. The resulting transgenic mice showed selective expression of the tat gene in the epidermis and, as early as 3-4 mo of age, showed extensive epidermal hyperplasia. Despite the restricted expression of the transgene in the epidermis, these mice went on to develop progressive dermal lesions with features characteristic of human Kaposi's sarcoma and thus confirming the involvement of the tat gene in this form of malignancy. We propose that HIV is responsible for at least some of the cutaneous manifestations observed in AIDS pts and offer differing mechanisms whereby the HIV tat gene may act on diverse target cells in the skin to induce uncontrolled proliferation both in culture and in animals.
Keywords: Acquired Immunodeficiency Syndrome/MICROBIOLOGY Animal *Cell Transformation, Neoplastic Cells, Cultured *Genes, tat Human HIV/*GENETICS HIV Long Terminal Repeat Keratinocytes/*CYTOLOGY/PATHOLOGY Mice Mice, Transgenic Skin Neoplasms/*GENETICS/PATHOLOGY ABSTRACT 920228
M9220883
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
